Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer

Summary Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and CAFs use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis functions to control CAF subtype identity when glutamine is limiting. Our data demonstrate that metabolic stress leads to an intrinsic inflammatory CAF (iCAF) program driven by MEK/ERK signaling. Utilizing in vivo models, we find that blocking macropinocytosis alters CAF subtypes and reorganizes the tumor stroma. Importantly, these changes in stromal architecture can be exploited to sensitize PDAC to immunotherapy and chemotherapy. Our findings demonstrate that metabolic stress plays a role in shaping the tumor microenvironment, and that this attribute can be harnessed for therapeutic impact. Graphical Abstract